Type 2 diabetes is a chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. The treatment of Type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy. For many patients, these regimens do not sufficiently control glycaemia during long term treatment, leading to a requirement of combination therapy within several years following diagnosis. However, co-prescription of two or more oral antidiabetic drugs may result in treatment regimens that are complex and difficult for many patients to follow. Combining two or more antidiabetic agents into a single tablet provides a potential means of delivering combination therapy without adding to the complexity of patients' daily regimens. Such formulations have been well accepted in other disease indications, such as hypertension (HYZAAR™ which is a combination of losartan potassium and hydrochlorothiazide) and cholesterol lowering (VYTORIN™ which is a combination of simvastatin and ezetimibe). The selection of effective and well-tolerated treatments is a key step in the design of a combination tablet. Moreover, it is essential that the components have complementary mechanism and compatible pharmacokinetic profiles. Examples of marketed combination tablets containing two oral antidiabetic agents include Glucovance™ (metformin and glyburide), Avandament™ (metformin and rosiglitazone), and Metaglip™ (metformin and glipizide).
Metformin represents the only oral antidiabetic agent proven to reduce the total burden of microvascular and macrovascular diabetic complications and to prolong the lives of Type 2 diabetes patients. Furthermore, metformin treatment is usually associated with the weight loss in overweight patients and with improvements in lipid profiles in dyslipidemic patients.
Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with Type 2 diabetes. Specific drugs currently in clinical trials for the treatment of Type 2 diabetes include MK-0431, vildagliptin (LAF-237), saxagliptin (BMS-47718), P93/01 (Prosidon), SYR322 (Takeda), GSK823093, Roche0730699, TS021 (Taisho), E3024 (Eisai) and PHX-1149(Phenomix). For example, oral administration of vildagliptin to human Type 2 diabetes patients has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbAIC levels. For reviews on the application of DPP-4 inhibitors for the treatment of Type 2 diabetes, reference is made to the following publications: (1) H.-U. Demuth. et al. “Type 2 diabetes-Theraphy with dipeptidyl peptidase IV inhibitors”, Biochim. Biophvs. Acta. 1751:33-44 (2005) and (2) K. Augustyns. et al. “Inhibitors of proline-specific dipeptidyl peptidases: DPP4 inhibitors as a novel approach for the treatment of Type 2 diabetes”, Expert Opin. Ther. Patants, 15: 1387-1407 (2005).